Project Summary A growing body of evidence in both animals and humans documents a strong interaction between sleep and pain. Chronic pain can impair sleep, while sleep disturbance can exacerbate pain. Among pain syndromes, headache has an especially close relationship with sleep: sleep disturbance is among the most commonly cited precipitants of migraine and other headaches, and, conversely, sleep is cited as a palliative for headache attacks by a large majority of migraineurs. However, the neurobiological basis for this interaction between headache and sleep is not understood, and there has been no study of this relationship in any animal model of headache. We now propose to address this gap in knowledge by investigating sleep behavior in a commonly used headache model, dural infusion of inflammatory mediators. Previously, we had observed that this stimulus results in an increase in resting behavior, during a 45-minute observation period following the dural infusion. To pursue this observation further, we have used EEG recording, and have made the surprising observation that the animals also exhibit periods of sleep during the observation period, which is not observed in the control animals. This observation is potentially of clinical significance for raising the novel idea that headache is itself somnogenic. We propose to pursue this observation, by investigating the interaction between dural stimulation and sleep behavior, in the following aims: 1. What is the effect of dural stimulation- induced ?headache? on sleep? This aim will test the hypothesis that dural stimulation-induced headache is somnogenic. Magnitude and time course of effects on both slow wave sleep and REM sleep will be determined. We will examine the effects of the following manipulations: a. time of day, which has potential clinical significance for understanding the impact on sleep of headache onset occurring during sleep vs waking. b. single dural infusion vs. repeated daily infusions for up to 7 days, relevant to understanding the transition to chronic headache; c. dural infusion vs stimulation of a superficial extracranial tissue, by subcutaneous injection of inflammatory mediators into the scalp. This will test the hypothesis that superficial noxious stimulation is arousing rather than somnogenic. 2. What is the effect of sleep on dural-stimulation-induced ?headache? (using facial allodynia as an indirect outcome measure of headache intensity)? This will test the hypothesis that decreased sleep results in an increase in the dural stimulation-induced facial allodynia, using the following manipulations to reduce sleep: a. 4-hr non-stressful sleep deprivation immediately before or after the dural infusion. b. Sleep reduction by cell-body-specific bilateral lesion of a recently discovered sleep center, the parafacial zone. An enhancement of the previously reported post-dural-infusion facial allodynia in animals with decreased sleep will be of potential clinical significance in relation to the observations that sleep loss can predispose to headache attacks, and that, after headache onset, sleep is therapeutic for resolving headache.